Cyclopentan opolyhydrophenanthrene derivatives and process of producing same



UNITED STATES PATENT OFFICE CYCLOPENTAN O POLYHYDROPHENAN- THRENEDERIVATIVES AND PROCESS OF PRODUCING SAME Rupert Oppenauer, Amsterdam,Netherlands, and Hans Kaegl, Basel, and Karl Miescher, Riehen,Switzerland, assignors, by mesne assignments,

to Ciba Pharmaceutical Products, Incorporated, Summit, N. J., acorporation of New Jersey N Drawing.

Application May 24, 1938, Serial No. 209,836. In the Netherlands May 29,1937 11 Claims.

According to this invention cyclopentanopolyhydrophenanthrenederivatives can be made by causing an am-dihalogen carboxylic acidderivative of the formula (01. zen-397.1)

pionyl, benzoyl, alkyl, aryl or aralkyl (such as trityl) or similargroups. If in the case oi polyketones keto-groups other than thatpresent in 17-position are to be protected before the reaction they areconverted into substituted enol- R groups (acetate, benzoate, tritylether, acetals, 5 and the like). r- As aza-dihalogen carboxylic acidderivatives there come into consideration for example substituted andunsubstituted esters and amides of dichloracetic acid, dichloroin whichR1 and R12 represent'halogen, R3 repre- 01 dibr m -propionie aciddjchloro-p-acy1oxysents hydrogen or a substituted or unsubstitutedpropiomc acids, -d1ch10r butyflc hyd o a o id ealboxyl up and R4chloromalonic acid, dichlorophenylacetic acid, dip fl y acid ester amidegroup 15 bromocyanacetic acid and the like, as well as the or a t e p,to act in Presence of nitriles corresponding with these acids. Asconnesium or a similar bivalent metal on a saturated densing agent th iused magnesium or um. or unsaturated 17-ketone of he eyelopentanelarbivalent metal, advantageously in the form of polyhydrophenanthreneseries. The reaction a dilute amalgam, for example an amalgam of pr du to ta d a dinst the p sent process 20 1 per cent strength. Thecondensation is admay be t eat d W h saponifying agent with vantageouslyconducted in presence of a solvent. simultaneous or P evi s eliminationof hydrogen Suitable solvents for this purpose are ethers such halide-orWater and the eelboxylic'acids thus as diethyl ether or anisole,hydrocarbons such as ta e may be ylated. But the halogen benzene,toluene, benzine or the like and also in atoms may also be rep a dbefore treating the some cases the ma-dihalogen carboxylic acid desamewith saponifylng a en s by ealboxylic acid rivative used for thereaction itself, forexample radicals. Thus 20-0 0 compounds of thecyelodichloracetic acid ethyl ester. The reaction may pe op y p Seriesare occur at ordinary temperature. Advantageously, tamed. however, thereacting mixture is at first cooled Am the Saturated and unsaturatedsomewhat and then gently heated, for example to tones of thecyclopentanopolyhydrophenanthrene t boiling point of ethyl ether whenthis is used series Serving a Parent materials for the inVenas solvent.If required the reaction may be contion the o ow ketOneS may be named yWay ducted under pressure. An excess of the condensof example:androstenolones, such'as dehydroing agent, for example magnesiumamalgam, androsterones, androstanolones such as androand/or an excess ofthe dihglogen carboxylic s o OeStrOneS- hexahydlo-oestmnesequiacidderivative is advantageously used for the lins, equilenins,androstenediones, androstanedicondensation, ones, adrenosterone andandrostane-l'l-one' and Th f n i scheme ill t t th reactions derivativesand stern-isomers of these compounds. involved in the present inventiontaking as ex- Should the parent material contain fr e hyamples thecondensation of an ester or ether of droxyl groups these are to beprotected by S dehydroandrosterone (I) with a dihalogen acetic sti ut oo e p e b est fl at on o e heriacid ester (scheme A) and of anandrostene 3:17- fication. For this purpose the hydroxyl groupsdione-3-enol-es'ter with an aza-dihalogen-promay be substituted by, forexample, acetyl, propicnic acid ester (scheme B):

fla UM Lia-000B III ma Baponifleation Saponifleation CH: CH: CH: OH: H 0

0 T g-coon ji -coon [N L/ E0 HO K Iva Decuboxylation ifirboxylation CH:CH!

n \--l c=o C0:

H y no v B on 0H; CH: cm cm Hal 0 -l3--C0.0. ifil A" V 1\ R o /CC0.0R R0 J I mi 4211. n --H.Hal

on. CH1 0 CH: cm 0 A QC-00.01% c-coon (1H1 Hl Saponlflcation n-o o- I mv Decarboxylation CH: CH:

CH Thus in the first reaction there are produced halogenhydrin acidderivatives, for example of the Formula II. These acid derivatives may,there are formed glycidic acid derivatives (for thereupon be treatedwith agents which bring about elimination of hydrogen halide whereby o vexample of Formula III) which pass into glycidi acids (for example ofFormula IV) when treated with saponifying agents, for example analcoholic alkali solution or an acid. The elimination of hydrogen halidemay or course be combined with the saponiflcation.

Also agents which split 01! water, for example a mineral acid, an acidanhydride or halide such as phosphorus pentoxide or thionyl chloride, anacid or neutral salt such as bisuliate or zinc chloride or the like maybe caused to act on the halogenhydrin acid derivatives obtained bycondensation with dihalogen acetic acid derivatives. There are thusobtained arm-unsaturated a-halogen carboxylic acid derivatives or thetype of Formula Illa and these can be converted likewise into freecarboxylic acids (apparently ozketocarboxylic acids IVa) by treatmentwith saponirying agents. The agents above mentioned also serve for thissaponification but it is usually advantageous to work in two stages byfirst treating the product with a salt of an organic acid such as analkali-acetate or alkalibenzoate and then saponifying the ester soobtained. The removal oi. water from and the saponification oi theunsaturated halogen carboxylic acid derivative may also be combined intoone operation.

The elimination of hydrogen halide or water from the chlorhydrin acidderivative and the saponification to produce the 20-oxo-compound mayeither occur in one stage, for example by the action of boilingalcoholic alkali, or in several stages, for example by treatment firstwith cold alcoholic alkali and then with hot alcoholic alkali or with anacid.

Hydrogen halide may also be split oil for example by the action of anorganic base, advantageously a tertiary base. If an ether of ahydroxyketone has been used as the parent material saponification isadvantageously brought about by means of an acid. r

The chlorohydrin acid derivative may also b caused to react with saltsof an organic acid, for example potassium acetate, sodium benzoate, andthe like. Thus an a.p-dihydroxy carboxylic acid derivative is obtainedwhich, when saponified, is converted into an a.p-dihydroxy acid, fromwhich a glycidic acid or an a-keto-acid can be prepared by separatingwater.

The free carboxylic acids are best decarboxylated by heating,advantageously in the presence of an organic base, especially a tertiarybase such as quinoline, quinaldine and the like, or of an acid forexample butyric acid, in the presence of a catalyst for example eopperora copper salt,

CH, CH:

obtained from an ether or ester of the dehydroandrosterone and an.-dichloropropionic acid derivative is heated together with a dimethyl-C-COOH aniline, the reaction product consists preferably of the knownN-pregnenolone. It instead of the dimethyl-aniline quinoline is used,nearly exclusively a new isomeric pregnenolone is obtained which is notidentical with the known iso-pregnenolone.

The intermediate products and final products obtainable in accordancewith the invention are in part compounds of therapeutic value or theyare useful for the preparation of such compounds.-

The following examples illustrate the invention, the parts being byweight:

Example 1 2.5 parts of magnesium are amalgamated with the aid or heatwith 250 parts of mercury in a current of hydrogen After cooling asolution of 6.6 parts of trans-dehydroandrosterone acetate in parts ofabsolute ether is added and 17.5 parts or a.a-dicliloropropionic acidethyl ester are added slowly drop by drop whilst stirring and coolingwith ice. The amalgam decomposes and a white precipitate separates. Whenthe main reaction is over the whole is heated to boiling for 1 hourlonger in a reflux apparatus. The reaction mixture is decomposed withice-water and hydrochloric acid and the etheral layer is separated anddried. After the ether has been evaporated the residue is treated withsteam whereby an easily volatile oil distils. The residue may' bedissolved in methanol and the solution is cooled whereby the ehlorhydrinester separates. When recrystallized from acetone it has the meltingpoint 162-l63 o. By heating the ester with half its weight of sodiumhydroxide dissolved in alcohol for a short time in a reflux apparatushydrogen chloride is split off and simultaneously the glycidic esterformed is saponified. The saponification solution is diluted with water,extracted with ether in order to remove non-acid constituents and thenacidified. The crude acid thus precipitated is filtered with suctionwashed with water and ether and recrystallized from dioxane. There isobtained a fine crystalline powder of melting point 186-187 C. whichaccording to analysis is A =-3-hydroxy-pregnene-17:20-oxide-20-carboxylic acid corresponding with Formula VI. 1 part of the acid isheated with 5 parts of quinoline for 10 minutes at 180-200 C. whereby itloses carbon dioxide. The cooled reactionprodnot is mixed with an excessof hydrochloric acid and the whole is extracted with ether. Afterevaporation of the ether there remains a yellowish crystalline powderwhich is recrystallized from alcohol of 60 per cent strength. There isthus obtained a product of melting point 193-194" C. and [a]n='-22. theacetate of which melts at 144 C. and shows an optical rotation of 27.5C. This product comprises a new A -3-hydroxypregnene-20-one, which iscalled neo-pregnenclone and which is levorotary, having a [odn 124 and amelting point of 223-224 C., in addition to the known pregnenolone whichis dextrorotary having a [u]n=+28.2 and a melting point of 192-l93 C. Ifthe decarboxylation is carried out in diaHryl aniline, a greaterproportion of the latter is produced.

an analogous manner pregnanol-(3) -ones- (20) are obtained from thecorresponding 3-acyloxy-17-hydroxy-20-chloropregnane-20-carboxylic acidesters by using as parent material, for example, esters of theandrosterone series.

Example 2 If dichloroor dibromo-acetic acid ester is used Example 3 1.25parts of magnesium are amalgamated with '75 parts of mercury and causedto react under 75 parts of benzene with 3.5 parts of A -androstene-3:17-dione-3-eno1-benzoate and 13 parts of al.01- dibromopropionic acidethyl ester. The whole is heated for several hours to complete thereaction. By working up in a manner analogous to that described inExample 1 there is obtained the chlor-hydrin ester of the enol-benzoate(Formula IIB) which'on treatment with alkalies yields a 3-keto-glycidicacid, hydrogen chloride, alcohol and benzoic acid being split off. Onheating this glycidic acid it loses carbon dioxide and is converted intoa product of melting point 208-209 C. containing a new A-pregnene-3z20-dione, called nee-progesterone.

Instead of the enol-benzoate there may be used an enol-ether of A-androstene-3zl'l-dione, for

example the 3-trityl-enol-ether, or the free A- androstene-3 17 -dioneitself.

Instead of a.a-dibromopropionic acid ethyl ester there may be used asreaction component for example an a.a-dihalogen-p-acyloxy-propicnic acidester;

Instead of an ester of the u.a-dihalogen carboxylic acid there maybeused an amide of this acid or the corresponding nitrile.

Example 4 33 parts of a.a-dibromophenylacetic acid ethyl ester arecaused to react in ether with 6.5 parts of zinc. After formation of theorgano-metallic compound 4 parts of trans-androsterone-benzoate areadded and the whole is heated for a long time on-the water. bath. Thebromhydrin ester I wherein X represents a member of the group consistingof COOR, CONH: and CN, R standing for an alkyl radical.

2. The cyclopentano-polyhydrophenanthrenes containing in the3-positionan acyloxy group and in the 1'7-position a hydroxyl group and the groupof the formula J alt-coon I HI wherein'R stands for an alkyl radical.

3. The compounds of the formula on. em 0H ICCOOR which is a levorotaryisomer of the known dextrorotary A '-pregneno1-3-one-20 and has aspecific index of optical rotation [a]n=124.

6. The process for the manufacture ofcyclopentanopolyhydrophenanthrene-derivatives comprising reacting a17-ketone of the cyciopentanopolyhydrophenanthrene series with a memberof the group of a.a-dil1a1ogen carboxylic acid-esters, -amides and-nitriles in presence of a metal of the group consisting of magnesiumand zinc.

7. The process for the manufacture ofcyclopentanopolyhydrophenanthrene-derivatives comprising reacting a3-acyloxy-17-ketone of the cyclopentano-polyhydrophenanthrene serieswith an a.a-dihalogen-propionic acid ester in presence of magnesium.

8. The process for the manufacture ofcyclopentanopolyhydrophenanthrene-derivatives comprising reacting a A-dehydro-androsterone-3- aeylate with an u.a-dil1alogen-propionic acidester in presence of amalgamated magnesium.

9. The process for the manufacture ofcyclopentanopolyhydrophenanthrene-derivatives comprising reacting a A=-dehydro-androsterone-3- acylate with an a.a-diha1ogen-propionic acidester in presence of amalgamated magnesium, splitting ofthydrogen-halide, saponifying and decarboxylating the carboxylic acidthus obtained.

10. The process for the manufacture ofcyclopentanopolyhydrophenanthrene-derivatives comprising reacting a A-dehydro-androsterone-3- aeylate with an a.a-dihalogen-propionic acidester in presence of amalgamated magnesium, splitting offhydrogen-halide, saponifying and decarboxylating the carboxylic acidthus obtained in the presence of quinoline.

11. The process for the manufacture of cyclopentanopolyhydrophenanthrenederivatives comprising reacting a A =-dehydroandrosterone-3- aeylatewith an a.a-dihalogen-propionic acid ester in presence of amalgamatedmagnesium, splitting of! hydrogen-halide, saponifying anddecarboxylating the carboxylic acid thus obtained in the presence of adialkyl aniline.

RUPERT OPPENAUER. HANS KAEGI. KARL MIESCHER.

